CS269728B1 - Method of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid's preparation - Google Patents
Method of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid's preparation Download PDFInfo
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- CS269728B1 CS269728B1 CS89304A CS30489A CS269728B1 CS 269728 B1 CS269728 B1 CS 269728B1 CS 89304 A CS89304 A CS 89304A CS 30489 A CS30489 A CS 30489A CS 269728 B1 CS269728 B1 CS 269728B1
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Abstract
Řešení se týká způsobu přípravy 7 -chlor-6-fluor-l~( 4-fluorfenyl)-1,4- -dihydro-4-oxochinolin-3-karboxylové kyseliny vzorce I CS 269728 B l vyznačující se tím, že se l-(4-aminofenyl)-7-chlor-6-fluor-l,4-dibydro-4-oxochinolin-3-karboxylová kyselina podrobí diazotaci v prostředí 30 až 70 % roztoku fluorovodíku v pyridinu a q'áeledujieí dediazonizaci zahřátím vzniklého roztoku na teplotu 50 až‘90 oc. Sloučenina vzoroe I i slouží jako meziprodukt pro přípravu antibakteriálního preparátu difloxacinu.The solution relates to a method of preparation 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4- -dihydro-4-oxoquinoline-3-carboxylic acid of Formula I CS 269728 B l characterized in that 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4-dibydro-4-oxoquinoline-3-carboxylic acid acid subject diazotization in 30 to 70% solution hydrogen fluoride in pyridine and dehydrogenation heating the resulting solution to temperature of 50 to 90 ° C. Compound of Formula I i it serves as an intermediate for the preparation of antibacterial preparation of difloxacin.
Description
CS 269 728 B1 1
Vynález se týká způsobu přípravy 7-chlor-6-fluor-l-(4-fluorfenyl)-1,4-dihydro-4--oxochinolin-3-karboxylové kyseliny vzorce I
Je znAAá vysoká účinnost řady substituovaných l-aryl-6-fluor-l,4-dihydro-4-oxo-chinolin-3-karboxylových kyselin proti Širokému spektru bakterií. Nejúčinnější látky ma-jí v poloze 7 zbytek cyklického aminu, často piperazinu, a v poloze 1 skupinu 4-fluorfe-nylovou (Hádl,S., Zikán, V.: Ďeskoslov. Parm. 36, 180, 1987). Klíčovým meziproduktempro přípravu .těchto látek je sloučenina vzorce I. Dosud známý způsob přípravy této lát-ky je obtížný a vychází z 2,4-diohloř-5-fluorbenzoové kyseliny, která je špatně dostupné(Chu, D.T.W. a Bpol. J. Med. Chem. 28, 1558, 1985).
Nevýhodu Obtížné přípravy sloučeniny vzorce I a obtížné dostupnosti výchozích su-rovin odstraňuje tento vynález. Sloučeninu vzorce I lze podle vynálezu připravit diazo-tací roztoku snadno dostupné l-(4-aminofenyl)-7-chlor-6-fluor-l,4-dihydro-4-oxochinolin--3-karboxylové kyseliny v 30 až 70% roztoku suchého fluorovodíku v pyridinu, pomocí alka-lického dusitanu a rozkladem takto vzniklého diazoniumfluoridu zahřátím reakční směsi nateplotu 50 až 90 °C, s výhodou na 70 °C.
Způsob přípravy podle vynálezu je jednoduchý a poskytuje žádanou látku v čistotěvhodné pro dalSí zpracování na difloxacin nebo podobné antibakteriální preparáty. Uvede-né příklady provedení uvádí dalSí podrobnosti, vynález však pouze ilustrují, nikoliv ome-zují. Příklad 1 K roztoku suchého fluorovodíku (12 g) v pyridinu (13 g) bylo při teplotě -20 °C přidáno1,66 g (5 mmol) l-(4-aminofenyl)-7-chlor-6-fluor-l,4-dihydro-4-oxochinolin-3-karboxylovékyseliny a směs byla míchána 30 minut za teploty místnosti. Po ochlazení na 0 °C bylopřidáno 0,42 g (6 mmol) dusitanu sodného a směs byla míchána 30 minut za teploty místnos-ti. Poté byla teplota poetupně během 30 minut zvýšena na 70 °C a při této teplotě bylareakční směs udržována 1 hodinu. Po ochlazení byla reakční směs nalita na 200 g ledu abyla ponechána do druhého dne stát, poté byl nerozpustný podíl odsát a promyt vodou. By-lo získáno 1,05 g látky (62 %) o t.t. 260 až 264 °C. Příklad 2 K roztoku suchého fluorovodíku (10 g) v pyridinu (5 g) bylo při teplotě 0 °C přidáno0,99 g (3 mmol) l-(4-aminofenyl)-7-chlor-6-fluor-l,4-dihydro-4-oxochinolin-3-karboxylo-vé kyseliny a směs byla dále zpracovávána stejným způsobem jako v přikladu 1. Bylo získá-no 0,6 g (60 %) látky o stejných vlastnostech jako v příkladu 1.
EN 269 728 B1 1
The present invention relates to a process for the preparation of 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula I
There is a high potency of a number of substituted 1-aryl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids against a wide variety of bacteria. The most active compounds at the 7-position are the cyclic amine residue, often piperazine, and the 4-fluorophenyl group at the 1-position (Hádl, S., Zikán, V .: Czechoslovak. Parm. 36, 180, 1987). A key intermediate for the preparation of these compounds is the compound of formula I. The prior art process for preparing this compound is difficult and is based on 2,4-dihydro-5-fluorobenzoic acid which is poorly available (Chu, DTW and Bpol. J. Med. Chem., 28, 1558 (1985).
The disadvantage of the difficult preparation of the compound of formula (I) and the difficulty in obtaining the starting materials are eliminated by the present invention. According to the invention, the compound of formula (I) can be prepared by diazotizing a solution of readily available 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 30-70% solution dry hydrogen fluoride in pyridine, with alkali nitrite and decomposition of the diazonium fluoride thus formed by heating the reaction mixture to a temperature of 50 to 90 ° C, preferably to 70 ° C.
The process of the invention is simple and provides the desired substance in a purifiable form for further processing to difloxacin or similar antibacterial preparations. The examples set forth further details, but the invention is merely illustrative, not limiting. Example 1 To a solution of dry hydrogen fluoride (12 g) in pyridine (13 g) was added 1.66 g (5 mmol) of 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4 at -20 ° C. -dihydro-4-oxoquinoline-3-carboxylic acid, and the mixture was stirred at room temperature for 30 minutes. After cooling to 0 ° C, 0.42 g (6 mmol) of sodium nitrite was added and the mixture was stirred for 30 minutes at room temperature. The temperature was then raised to 70 ° C over a period of 30 minutes and the reaction mixture was kept at this temperature for 1 hour. After cooling, the reaction mixture was poured onto 200 g of ice and allowed to stand for another day, then insoluble matter was sucked off and washed with water. 1.05 g of material (62%) was obtained, mp 260-264 ° C. EXAMPLE 2 To a solution of dry hydrogen fluoride (10 g) in pyridine (5 g) was added 0.99 g (3 mmol) of 1- (4-aminophenyl) -7-chloro-6-fluoro-1, 4-g at 3 ° C. dihydro-4-oxoquinoline-3-carboxylic acid and further worked up in the same manner as in Example 1. 0.6 g (60%) of the same properties as in Example 1 were obtained.
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CS89304A CS269728B1 (en) | 1989-01-16 | 1989-01-16 | Method of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid's preparation |
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CS89304A CS269728B1 (en) | 1989-01-16 | 1989-01-16 | Method of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid's preparation |
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CS30489A1 CS30489A1 (en) | 1989-09-12 |
CS269728B1 true CS269728B1 (en) | 1990-05-14 |
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